期刊
CELL DEATH AND DIFFERENTIATION
卷 18, 期 12, 页码 1865-1875出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.57
关键词
p53; ubiquitination; E3 ligase
资金
- Korea Institute of Radiological and Medical Sciences, Seoul, Korea
- Ministry of Education, Science, and Technology [2010-0020372, 2010-0015732, 2010-0017593, 20100018768]
- Ministry of Knowledge Economy [R-2006-1-043]
- Ministry for Health, Welfare and Family Affairs [0720072]
Following DNA damage, p53 translocates to the cytoplasm and mitochondria, where it triggers transcription-independent apoptosis by binding to Bcl-2 family proteins. However, little is known about how this exonuclear function of p53 is regulated. Here, we identify and characterize a p53-interacting protein called Hades, an E3 ligase that interacts with p53 in the mitochondria. Hades reduces p53 stability via a mechanism that requires its RING-finger domain with ubiquitin ligase activity. Hades polyubiquitinates p53 in vitro independent of Mdm2 and targets a critical lysine residue in p53 (lysine 24) distinct from those targeted by Mdm2. Hades inhibits a p53-dependent mitochondrial cell death pathway by inhibiting p53 and Bcl-2 interactions. These findings show that Hades-mediated p53 ubiquitination is a novel mechanism for negatively regulating the exonuclear function of p53. Cell Death and Differentiation (2011) 18, 1865-1875; doi:10.1038/cdd.2011.57; published online 20 May 2011
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